The extreme phenotype of the pancreatic acinar cell, a digestive enzyme-producing factory that devotes 90% of its protein synthesis to secretory output, must be actively buffered and maintained in the face of physiological and pathological stressors. Indeed, the exocrine pancreatic maladies of pancreatitis and ductal adenocarcinoma derive, in part, from the malleable identity of the acinar cell. We have identified a handful of ke acinar-restricted transcription factors that establish and likely maintain the unique identity of te pancreatic acinar cell. The identification of PTF1A, RBPJL, NR5A2, FOXA2 and GATA4 as master Transcription Factors (mTFs) is based on their high and pancreatic acinar cell-restricted expression, crucial roles for specifying the acinar lineage during development, binding to transcriptional control sequences of thousands of acinar genes, pleiotropic effects on the acinar transcriptome (especially acinar-specific genes), and collaboration with second tier transcription factors in feed-forward regulatory schemes. The research proposed will investigate the molecular regulatory strategies and molecular mechanisms by which the mTFs maintain long-term acinar cell- identity and prevent chronic cell fate changes associated with disease. We propose the following three Specific Aims. Aim 1 will verify the pleiotropic functional importance of the putative mTFs by testing whether each mTF is necessary for the expression of all target genes, whether binding of each mTF to the transcriptional enhancers of several target genes is necessary for the in vivo activities of the enhancers, and whether the mTFs mediate much of their control through feed-forward co-regulation with second tier scaling transcription factors such as MIST1 and XBP1. Aim 2 will build on the foundation of Aim 1 to determine the molecular actions of the mTFs during transient metaplasia induced by caerulein-induced acute pancreatitis, and establish how the mTFs act to re-establish identity and suppress chronic inflammation after injury. Aim 3 will test directly whether and how the mTFs resist the severe disruption of cell-identity associated with oncogenic KRAS-induced acinar-ductal reprogramming, a prerequisite step of adenocarcinoma initiation, and determine whether sustained activation of mTF function could serve as a preclinical differentiation therapy in a model of this deadly cancer. These studies will provide both basic and translational insights into the regulatory mechanisms that maintain acinar cell identity, and will facilitate therapeutic interventions targeting these mechanisms in pancreatitis and ductal adenocarcinoma.